Substituted thiazoles for preventing and/or treating cell or tissue necrosis

A method for ameliorating, inhibiting, or reducing the incidence of necrotic cell death in a subject, comprising administering to a subject in need thereof a therapeutically effective amount of a compound of Formula II:

• or a pharmaceutically acceptable salt thereof,
• wherein:
• G1 is piperidinyl, optionally substituted with one or more substituents independently selected from the group consisting of halogen, NO2, CN, C1-C6 alkyl, C1-C6 haloalkyl, NH2, OH, OC1-C6 alkyl, C(O)H, C(O)C1-C6 alkyl, C(O)NH2, C(O)OH, and C(O)OC1-C6 alkyl;
• and
• G3 is:
• wherein:
• G2 is pyrrolidinyl or piperazinyl, each optionally substituted with one or more substituents independently selected from the group consisting of halogen, NO2, CN, C1-C6 alkyl, C1-C6 haloalkyl, NH2, OH, OC1-C6 alkyl, C(O)H, C(O)C1-C6 alkyl, C(O)NH2, C(O)OH, and C(O)OC1-C6 alkyl;
• wherein the subject suffers from cellular necrosis of a cell selected from the group consisting of a bone cell, a brain cell, a cardiac cell, a cartilage cell, an embryonic cell, an epidermal cell, an epithelial cell, a fibroblast, a gastrointestinal cell, a glial cell, a gonadal cell, a hematopoetic cell, a kidney cell, a liver cell, a lung cell, a lymphocyte, a macrophage, a muscle cell, a neuronal cell, a pancreatic cell, a parenchymal cell, a retinal cell, a spleen cell, and a stem cell.

A method for down-regulating the expression of and/or inhibiting the activity of at least one kinase selected from the group consisting of cathepsin C, chymotrypsin-like elastase family member 1, and chymotrypsin-like elastase family member 3 in a subject, comprising administering to a subject in need thereof a therapeutically effective amount of a compound of Formula II:

• or a pharmaceutically acceptable salt thereof,
• wherein:
• G1 is piperidinyl, optionally substituted with one or more substituents independently selected from the group consisting of halogen, NO2, CN, C1-C6 alkyl, C1-C6 haloalkyl, NH2, OH, OC1-C6 alkyl, C(O)H, C(O)C1-C6 alkyl, C(O)NH2, C(O)OH, and C(O)OC1-C6 alkyl;
• and
• G3 is:
• wherein:
• G2 is pyrrolidinyl or piperazinyl, each optionally substituted with one or more substituents independently selected from the group consisting of halogen, NO2, CN, C1-C6 alkyl, C1-C6 haloalkyl, NH2, OH, OC1-C6 alkyl, C(O)H, C(O)C1-C6 alkyl, C(O)NH2, C(O)OH, and C(O)OC1-C6 alkyl.

An in vitro or ex vivo method for inhibiting the incidence of necrotic cell death or reducing the incidence of necrotic cell death, comprising contacting the cell with a compound of Formula II:

• or a pharmaceutically acceptable salt thereof,
• wherein:
• G1 is piperidinyl, optionally substituted with one or more substituents independently selected from the group consisting of halogen, NO2, CN, C1-C6 alkyl, C1-C6 haloalkyl, NH2, OH, OC1-C6 alkyl, C(O)H, C(O)C1-C6 alkyl, C(O)NH2, C(O)OH, and C(O)OC1-C6 alkyl;
• and
• G3 is:
• wherein:
• G2 is pyrrolidinyl or piperazinyl, each optionally substituted with one or more substituents independently selected from the group consisting of halogen, NO2, CN, C1-C6 alkyl, C1-C6 haloalkyl, NH2, OH, OC1-C6 alkyl, C(O)H, C(O)C1-C6 alkyl, C(O)NH2, C(O)OH, and C(O)OC1-C6 alkyl.